Abstract Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). It occurs because immunocompetent donor T cells in the allograft recognize the genetically disparate host as foreign and attack the transplant recipient's tissues. While genetic incompatibility between the donor and the recipient is the primary factor that determines the extent of the alloimmune response, non-genetic factors can also influence the incidence and severity of GVHD. Recent advances in immunology establish that environmental factors, including dietary micronutrients, actively participate in modifying a variety of immune responses and influence the susceptibility of experimental animals and humans to autoimmune and inflammatory diseases. The role of dietary micronutrients in GVHD pathogenesis is poorly understood. We and others recently identified retinoic acid (RA), the active metabolite of vitamin A, as a key molecule in facilitating the development of intestinal GVHD. These studies reveal how the metabolite of a single common vitamin can profoundly influence GVHD risk after allogeneic HSCT. These findings prompted us to examine the potential role of other dietary micronutrients in modulating the alloimmune response. The objective of this grant is to define how vitamin D influences the development of GVHD. We will test the novel hypothesis that enhancing intestinal vitamin D receptor (VDR) signaling strengthens mucosal epithelial barrier to mitigate GVHD. This hypothesis is based on our exciting preliminary data demonstrating that selectively enhancing intestinal VDR signaling protects against GVHD in experimental mice. We will combine genetic, pharmacologic, and dietary approaches to examine this hypothesis. Studies in Aim 1 will define the role of intestinal epithelial VDR signaling in modulating alloimmunity after HSCT. Aim 2 will determine how therapeutic targeting of vitamin D/VDR pathway mitigates GVHD risk. We expect that results from these studies will advance our understanding with respect to the role of vitamin D, as an environmental factor, in GVHD pathogenesis. Furthermore, these studies will provide preclinical data that support the use of vitamin D and its analogs as simple and cost-effective adjunct therapies with minimal side effects for GVHD prevention and/or treatment.